In healthy cells, a balance of redox reactions maintains a physiologically appropriate environment for various cellular functions related to growth, differentiation, activity, and death. The proper coordination of such functions ensures homeostasis and the health of cells. Research has shown that alterations in cellular redox status affect activities such as cellular signaling, suggesting that altering the cellular redox status could also affect cellular activation, which results from certain cellular signals (U.S. Pat. No. 5,994,402). Altering the intracellular redox state by depleting cells of glutathione (GSH), an endogenous “redox agent,” has also been shown to protect cells from certain injury and to promote their survival (U.S. Pat. No. 5,994,402), again suggesting a link between alterations in the cellular redox state and cellular functions.
An imbalanced redox state, even if not the cause of a particular disease condition, may facilitate that condition by providing an “unhealthy” environment in which necessary cellular functions become impaired. Cellular redox status may become impaired in numerous disease conditions. Under the stress of a disease state, the rate of redox reactions increases or decreases as needed by the cell. Significant or prolonged deviations in the intracellular redox status disable cellular processes, including defense mechanisms. When such cellular functions are impaired, the survival of the cell becomes uncertain. Maintenance of the proper redox status is thus critical to the fate of the cell.
To counter and correct disturbances in the redox status, cells require agents that can modulate redox imbalances, to facilitate reduction or oxidation reactions as appropriate. Agents currently available for correcting redox imbalances are inadequate in that they are labile, quickly oxidized, or unable to translocate to the proper region of the cell. Examples of such exogenous redox agents include cysteine, reduced lipoates or thiols, glucocorticoids, and other antioxidants. Redox agents that remain stable, active, and functional in the cellular environment are necessary.
Phthalazinediones and phthalazinedione derivatives have been described as effective against certain conditions associated with redox imbalances such as inflammation, cancer, arrhythmia, hyperlipidemia, and hypoxia (U.S. Pat. Nos. 6,686,347; 6,489,326; 5,874,444; 5,543,410; 5,512,573; 4,861,778; 4,250,180; Hall et al., Biomed. Biochim. Acta. Al: 423-433 (1988); Hall et al., J Pharm. Pharmacol. 41: 394-397 (1989); Hall et al., Anticancer Drugs. 3: 55-62 (1992); Burner et al., Int. J. Tissue React. 18: 47-55 (1996)). However, toxicity and the lack of pharmacological activity of certain phthalazinediones, including 2,3-dihydrophthalazine-1,4-dione and 5-amino-2,3-dihydrophthalazine-1,4-dione, were also noted (U.S. Pat. Nos. 6,489,326; 5,543,410; 5,512,573).